1. Field of the Invention
This invention relates to the field of immunology and specifically to monoclonal antibodies which bind to a specific sequence within the C5a receptor.
2. Description of Related Art
In man, and in most animals, the complement system is composed of a group of proteins that are normally present in serum in an inactive state. When activated, these proteins participate in a coordinated series of reactions. Activation of the complement system results in enzymatic cleavage of complement proteins producing numerous subfragments which possess a wide range of biologic activities required for host defense, including the elimination of invading microorganisms. During an inflammatory process, local production of complement-derived mediators result in increased vascular permeability, leukocyte adherence to endothelial and vascular tissue, and a chemotactic gradient that induces neutrophil (PMN) migration into the inflammatory site. In addition to beneficial aspects of the inflammatory process, systemic and/or chronic inflammatory processes have been associated with a variety of immune disease states. C5a is one of the best described and most potent proinflammatory mediators derived from the complement system. C5a has been shown to be spasmogenic (Stimler, et al., J. Immunol. 126:2258, 1981), chemotactic (Hugli, et al., Adv. Immunol. 26:1, 1978), to increase vascular permeability (Shin, et al., Science 162:361, 1968), and to induce the release of pharmacologically active mediators from numerous cell types (Grant, et al., J. Immunol. 114:1101, 1975; Goldstein, et al., J. Immunol. 113:1583, 1973; Schorlemmer, et al., Nature 261:48, 1976). Most recently, C5a has been shown to directly or indirectly induce cytokine release from macrophages and to augment humoral- and cell-mediated immune responses in vitro. Combined, these studies indicate that C5a possesses multiple biologic activities important in host defense and may also play a role in inflammatory disease processes. Many cell types possess receptors for C5a, including PMNs, macrophages, mast cells and platelets.
Numerous antibodies directed to PMN surface determinants have been generated to study inflammatory mediator-cell interactions. The majority of these monoclonal or polyclonal antibodies have lacked specificity. Some have shown limited specificity, primarily those involving N-formyl chemotactic peptide (f-MLF)-receptor interactions. These antibodies to f-MLF have been shown to suppress or mimic ligand-induced chemotaxis, phagocytosis, adherence, exocytosis, enzyme release, or the oxidative burst. To date, generation of antibodies specific for the C5a receptor has proven to be problematic. Although the solubilization of a functional C5a receptor from human PMN has been achieved, attempts to purify sufficient quantities of C5a receptor to homogeneity for the production of antibodies has failed.
The availability of C5a receptor-specific neutralizing antibodies would provide not only an important Tool for dissecting the mechanisms of C5a-mediated cellular activation, but would also represent an important therapeutic reagent, useful in controlling inflammatory and autoimmune diseases. The present invention answers this need.